Alcohol use disorder (AUD) is a leading cause of morbidity and mortality worldwide, characterized by cycles of heightened craving and excessive, uncontrolled consumption of alcohol despite progressive decline in physical and mental health. Voluntary alcohol consumption is influenced by a variety of environmental and genetic factors, including circadian clock genes, whose effects are modulated in a sex-specific manner. The sex-specific role of clock genes in alcohol drinking was identified through selective ablation of Bmal1 and Per2 from neurons of the mouse striatum; however, the contribution of specific striatal subregions to the observed drinking behavior remains unclear. Thus, alcohol intake and preference were investigated in male and female mice with a conditional knockout of Bmal1 or Per2 from cells in the nucleus accumbens (NAc), a key area of the brain's reward center. Alcohol consumption and preference were increased in male and female mice with a conditional knockout of Bmal1, whereas the deletion of Per2 increased consumption and preference in males only. The changes in alcohol consumption can be attributed to the manipulation of the circadian clock genes in the NAc exclusively, because affective behaviors were largely unchanged. The results show that Bmal1 and Per2 in the NAc are negative regulators of alcohol drinking in mice, with sex-dependent differences in their effects.
